N-Ethylhexedrone (also known as NEH and hexen) is a lesser-known novel stimulant substance of the cathinone class. N-Ethylhexedrone is a derivative of hexedrone and is part of a diverse group of compounds called the substituted cathinones. Little is known about its pharmacology, although it likely acts by increasing levels of norepinephrine and dopamine in the brain.

The original synthesis date of N-ethylhexedrone is unknown. It appears to have emerged on the online research chemical market in late 2015. It is an example of a novel psychoactive substance specifically chosen to mimic the features of prohibited substances and bypass drug laws. It is one of a number of substances collectively referred to in popular culture as "bath salts".[citation needed]

History and culture

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N-Ethylhexedrone was first identified in a sample from the Belgian Customs laboratory which was received at the JRC on November 2015. In January 2016, it was identified at the JRC in a sample provided by French Customs. Subsequently, in February 2016, the EMCDDA received notifications of the identification of this substance from other countries, such as Sweden, The Netherlands, France, Belgium and Slovenia.[1]

Chemistry

N-ethylhexedrone is a molecule of the cathinone chemical class. The term "substituted cathinone" refers to a broad array of substances based on cathinone, the principally active constituent of the khat plant. Cathinone is principally constituted of a amphetamine core (a phenethylamine core with an alkyl group attached to the alpha carbon) and an oxygen group attached to the beta carbon. Cathinones are also known as the beta-ketone (βk) (double-bonded oxygen to the β-carbon) analogs of amphetamines.

Notably, the cathinone backbone can be modified in three different places to create hundreds of possible compounds, which include substituents such as
on the aromatic ring, the alpha carbon, or the amine group.[2]

Pharmacology

Very little data exists on the human pharmacokinetics and pharmacodynamics of N-ethylhexedrone and other substituted cathinones. Like amphetamines, synthetic cathinones exert their stimulating and sympathomimetic effects via increasing synaptic concentration of catecholamines such as dopamine, serotonin and norepinephrine. These molecules are able to inhibit monoaminereuptake transporters producing a decreased clearance of the neurotransmitters from the synapse. Furthermore, they may cause release of biogenic amines from intracellular stores.[3]

Synthetic cathinones are generally less able than amphetamines to cross the blood–brain barrier because the beta-keto group causes an increase in polarity. Unlike other synthetic cathinones, pyrrolidine derivatives have a higher ability to cross the blood–brain barrier because the pyrrolidine ring confers a low polarity to these molecules. The studies on the metabolism of synthetic cathinones have shown that they are N-demethylated, the keto group is reduced to hydroxyl and ring alkyl groups are oxidised.[4]

Subjective effects

User reports suggests that N-ethylhexedrone has more side effects compared to other stimulants like mephedrone or NEP. This can lead to excessive redosing, sobriety delusions and toxicity, which can eventually lead to highly uncomfortable experiences. The effects of vaporized N-ethylhexedrone are reported to be much stronger and more euphoric with less side effects than when insufflated or taken orally, but extreme care should be taken with this route of administration due to the degree it promotes compulsive and reckless use.

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWikicontributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Stimulation - N-ethylhexedrone is reported to be be moderately to extremely stimulating and energetic.

Spontaneous bodily sensations - As with related cathininones, it is commonly reported that medium to high doses of N-ethylhexedrone can produce a pleasurable "body high" characterized by pleasant tingling sensations, which are stronger than that of amphetamine but weaker than a-PVP.

Teeth grinding - This component can be considered to be less intense when compared with that of MDMA and more similar to the teeth-grinding that can result from general cathinone use like a-PHP or NEP.

Cognitive effects

The headspace of N-ethylhexedrone is typically described as extreme mental stimulation accompanied by a powerful sense of euphoria.

Auditory effects

After effects

N-ethylhexedrone's comedown is usually described as more slow and less dysphoric than the same effect found within MDMA or methamphetamine but harsher than that of NEP.
The effects which occur during the offset of a stimulant experience generally feel negative and uncomfortable in comparison to the effects which occurred during its peak. This is often referred to as a "comedown" and occurs because of neurotransmitter depletion. Its effects commonly include:

Toxicity and harm potential

The toxicity and long-term health effects of recreational N-ethylhexedrone use do not seem to have been studied in any scientific context and the exact toxic dosage is unknown. This is because N-ethylhexedrone has a very brief history of human usage.

Early anecdotal reports from those who have tried N-ethylhexedrone suggests that there do not seem to be any negative health effects attributed to simply trying it at low to moderate doses by itself and using it in a sparing and controlled fashion (but nothing can be completely guaranteed).

Some users have reported N-ethylhexedrone to be caustic to the nasal membrane when it is insufflated.[citation needed]

Tolerance and addiction potential

As with other stimulants, the chronic use of N-ethylhexedrone can be considered moderately addictive with a high potential for abuse and seems to be readily liable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage.

Tolerance to many of the effects of N-ethylhexedrone develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the total absence of further consumption). N-ethylhexedrone presents cross-tolerance with all noradrenergic and dopaminergicstimulants, meaning that after the consumption of N-ethylhexedrone all stimulants will have a reduced effect.

Psychosis

Abuse of compounds within the stimulant class at high dosages for prolonged periods of time can potentially result in a stimulant psychosis that may present with a variety of symptoms (e.g., anxiety and paranoia, hallucinations, or delusions).[5] A review on treatment for (dextro)amphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[6][7] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[8]

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become harmful and even life-threatening when taken with other substances. The following section lists some known dangerous combinations, but it may not include all of them. Furthermore, a combination that seems to be harmless in low doses can still greatly increase the risk of injury or death when the doses are slightly increased. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from Tripsit.

Alcohol - Alcohol can be dangerous to combine with stimulants due to the risk of accidental over-intoxication. Stimulants mask the sedative effects of alcohol, which is the main factor people use to assess their degree of intoxication. Once the stimulant wears off, the depressant effects of alcohol are left unopposed, which can result in blackouts and respiratory depression. If combined, one should strictly limit themselves to only drinking a certain amount of alcohol per hour.

DXM - Combinations with DXM should be strictly avoided due to DXM's effects on serotonin and dopamine reuptake. This can lead to panic attacks, hypertensive crisis, or serotonin syndrome.

MXE - Combinations with MXE may dangerously elevate blood pressure and increase the risk of psychosis.

Tramadol - Tramadol lowers the seizure threshold.[9] Combinations with stimulants may further increase this risk.